The development of a successful HIV vaccine will require induction of neutralizing antibodies that can protect from infection by a broad range of HIV isolates. Although antibody responses can be generated as a result of vaccination or infection, these antibodies often recognize only immunodominant, highly variable epitopes that do not confer neutralizing protection. Broadly neutralizing antibodies (BNA) that are capable of neutralizing HIV across clades have been isolated from HIV patients that sustain high CD4 numbers, and low viral titers, over many years. Several of the BNA isolated from this long-term non-progressor (LTNP) population are also reactive to self-antigens, suggesting a relationship with autoreactive B cell development. The B cell source of HIV BNA is unclear but the above observations indicate that these cellular precursors must exist in these patients and should be identifiable. This goal will require fine discrimination of specific B cell subsets and powerful screening technology both of which are available in our laboratory. Accordingly, we propose to identify the cellular source of HIV BNA and determine if autoreactive B cells are enriched for HIV BNA. Discreet B cell subsets expressing validated surface markers will be isolated from healthy patients and those with HIV or Systemic Lupus Erythematosis, expanded, and evaluated for the production of HIV BNA. The results will be important to define the B cell subsets that should be targeted by future vaccines. The information obtained will accordingly inform the design of specific antigen preparations and adjuvant strategies to preferentially stimulate the BNA-producing B cell subsets to become long-lived plasma cells. The development of an effective vaccine to prevent HIV infection will require a better understanding of how to generate antibodies that will neutralize the virus. Similarities may exist between B cells that produce antibodies that prevent HIV infection and those that are found in patients with Lupus. We propose to identify the B cells that produce HIV neutralizing antibodies.